The present invention relates to a pharmaceutical composition comprising a drug and polymer spray-coated onto a meltable core.
It is well known that poorly water soluble drugs may be formulated as a solid amorphous dispersion of a drug in a polymer to improve the bioavailability of poorly soluble drugs. Preferred solid amorphous dispersions are formed by spray drying. Such solid amorphous dispersions are also referred to as molecular dispersions. A drawback of such spray dried dispersions is that the particles resulting from the spray-drying process are often very small (typically less than 100 microns in diameter) and have high specific volume (typically greater than 3 cm3/g). These properties make spray dried dispersions difficult to handle, and therefore complicate formulation of such dispersions into dosage forms suitable for oral delivery.
One approach to increasing the size and density of such solid amorphous dispersions is to spray-coat the drug and polymer onto an inert core. For example, the drug and polymer may be spray-coated onto an inert sugar sphere or microcrystalline cellulose. See, e.g., WO 02/38128. However, spray-coating such materials presents several problems. First, conventional sugar cores and the like are friable. Such materials have a tendency to break apart into smaller pieces in the fluid bed during the coating process. The fine material can be swept up into the gas stream, resulting in an inefficient coating process. In addition, the average core size tends to decrease as the coating time increases, resulting in a size distribution that changes over time. Since the release rate of the drug is dependent on the surface area of the multiparticulate, the dissolution rate of the spray-coated multiparticulates will be a function of the coating time. This can lead to non-reproducible dissolution rates from spray-coated multiparticulates due to slight differences in coating conditions from batch to batch. Conventional sugar cores and the like also tend to have rough, irregular surfaces, which can be difficult to coat uniformly.
Another problem associated with spray-coating on to conventional excipients is that the drug dissolution rate from such multiparticulates can be slow. Dissolution rate is dependent on the size of the multiparticulate and composition of the amorphous dispersion layer. It is desired to form small cores to coat, since smaller multiparticulates generally have higher dissolution rates. However, conventional sugar cores and the like are difficult to obtain in small sizes. In addition, surface irregularities tend to increase as the size of these particles decrease, making uniform coating difficult.
Another problem associated with sugar cores is that the sugar can act as an osmogen. When the particle is administered to an aqueous use environment, the particle can absorb water. The sugar core may rapidly absorb water, causing the multiparticule to rupture and prematurely release the drug.
What is therefore desired is a composition comprising a solid amorphous dispersion of drug and polymer coated onto a small, smooth inert core to provide a multiparticulate that has a size and density that facilitates processing of the dispersion into oral dosage forms, and that also allows the drug dissolution rate and release rate of the drug to be adjusted.